tbuckley/cabot-search huggingface dataset:
Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice
Authors: Barbara K. Mathiesen, Leo M. Miyakoshi, Christopher R. Cederroth, Evangelia Tserga, Corstiaen Versteegh, Peter A. R. Bork, Natalie L. Hauglund, Ryszard Stefan Gomolka, Yuki Mori, Niklas K. Edvall, Stephanie Rouse, Kjeld Møllgård, Jeffrey R. Holt, Maiken Nedergaard, Barbara Canlon
Journal: Science Translational Medicine (2023)

Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 ( Slc17A8 ), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8 −/− mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.
Stalled global progress on preventable maternal deaths needs renewed focus and action
Authors: Clara Menendez, Tacilta Nhampossa, Diane Fifonsi Gbeasor-Komlanvi, Valentina Buj de Lauwerier, Gagan Gupta, Flavia Bustreo
Journal: BMJ (2023)

goal on preventable maternal mortality, write Clara Menendez and colleagues
Commentary
Authors: Alanna Ebigbo
Journal: Endoscopy (2023)

Underwater endoscopic mucosal resection (UEMR) of gastrointestinal lesions is gaining increasing attention. Various studies have demonstrated the potential of UEMR and, in certain situations, its superiority over conventional EMR. An interesting application of underwater endoscopy, shown here by Yamamoto & Parra-Blanco, is the complete underwater closure of a UEMR defect. The concept of underwater clipping is easy to understand: when the intestinal lumen is filled with water, the tension on the mucosal defect is considerably reduced. Compared with the situation under gas, the EMR defect shrinks in size and its edges are more easily grasped by the clips, making complete closure easy even in larger-size lesions. Underwater clipping can be applied in all segments of the gastrointestinal tract. Hopefully, this video demonstration will encourage interventional endoscopists to use underwater techniques more often for the benefit of their patients.
Anticoagulation Conundrum in Acute Ischemic Stroke with Atrial Fibrillation
Authors: Ken Uchino
Journal: New England Journal of Medicine (2023)

Decades ago, before the days of thrombolysis for ischemic stroke, many patients with acute ischemic stroke routinely received anticoagulation therapy. This practice is now less common, and the question is now when to start anticoagulation for long-term prevention of secondary stroke, particularly in patients with atrial fibrillation. When is the risk of a hemorrhagic complication of anticoagulation balanced by the beneficial effect of prevention of recurrent stroke? Early randomized trials focused on rapid anticoagulation with the use of heparin or low-molecular-weight heparin — agents that were associated with a risk of hemorrhage.1 In the past decade, observational studies of direct . . .
The application of underwater endoscopic mucosal resection for superficial duodenal tumors
Authors: Jixiang Liu, Shukun Yao
Journal: Endoscopy (2023)

See also: Outcomes of endoscopic resection for superficial duodenal tumors: 10 years’ experience in 18 Japanese high volume centersEndoscopy 2022; 54(07): 663-670DOI: 10.1055/a-1640-3236 See also: Reply to Drs. Liu and YaoEndoscopy 2023; 55(07): 684-684DOI: 10.1055/a-2042-9806
Case 20-2023: A 52-Year-Old Man with a Solitary Fibrous Tumor and Hypoglycemia
Authors: Tara E. Soumerai, Gregory M. Cote, Reece J. Goiffon, Armen I. Yerevanian, Albert L. Sy
Journal: New England Journal of Medicine (2023)

A 52-year-old man with a metastatic solitary fibrous tumor was admitted for hypoglycemia. Levels of insulin, C-peptide, and β-hydroxybutyrate were undetectable. A diagnosis was made.
PET imaging of TREM1 identifies CNS-infiltrating myeloid cells in a mouse model of multiple sclerosis
Authors: Aisling M. Chaney, Haley C. Cropper, Poorva Jain, Edward Wilson, Federico Simonetta, Emily M. Johnson, Israt S. Alam, Ian T.J. Patterson, Michelle Swarovski, Marc Y. Stevens, Qian Wang, Carmen Azevedo, Sydney C. Nagy, Javier Ramos Benitez, Emily M. Deal, Hannes Vogel, Katrin I. Andreasson, Michelle L. James
Journal: Science Translational Medicine (2023)

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the 64 Cu-radiolabeled TREM1 antibody–based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)–PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1 + cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis
Authors: Geert D’Haens, Marla Dubinsky, Taku Kobayashi, Peter M. Irving, Stefanie Howaldt, Juris Pokrotnieks, Kathryn Krueger, Janelle Laskowski, Xingyuan Li, Trevor Lissoos, Joe Milata, Nathan Morris, Vipin Arora, Catherine Milch, William Sandborn, Bruce E. Sands
Journal: New England Journal of Medicine (2023)

Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. Download a PDF of the Research Summary. We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.) QUICK TAKE VIDEO SUMMARYMirikizumab for Ulcerative Colitis 02:25
Can a high-quality screening colonoscopy decrease the need for subsequent surveillance colonoscopies?
Authors: Katarzyna M. Pawlak
Journal: Endoscopy (2023)

Colorectal cancer (CRC) is the third most common cancer worldwide, with 2 million new cases diagnosed in 2020 and approximately one million deaths yearly [1]. Moreover, the International Agency for Research on Cancer estimates that by 2040, the global burden of CRC will have increased by 56 %, reaching 3 million new cases per year [1]. Screening and surveillance colonoscopies, which allow for polyp detection and removal, are critical in lowering CRC incidence. However, surveillance examinations account for up to 40 % of all colonoscopies, and incorrect surveillance accounts for one-third of the workload in CRC screening programs [2] [3]. As a result, updated surveillance recommendations that optimize colonoscopy services without harming patients should be considered. Although the ideal strategy is currently unknown, ongoing investigations are evaluating potential criteria to determine which patients benefit the most from surveillance and the appropriate time frame between subsequent colonoscopies [4].
Lazertinib Versus Gefitinib as First-Line Treatment in Patients With <i>EGFR</i>-Mutated Advanced Non–Small-Cell Lung Cancer: Results From LASER301
Authors: Byoung Chul Cho, Myung-Ju Ahn, Jin Hyoung Kang, Ross A. Soo, Thanyanan Reungwetwattana, James Chih-Hsin Yang, Irfan Cicin, Dong-Wan Kim, Yi-Long Wu, Shun Lu, Ki Hyeong Lee, Yong-Kek Pang, Anastasia Zimina, Chin Heng Fong, Elena Poddubskaya, Ahmet Sezer, Soon Hin How, Pongwut Danchaivijitr, YuKyung Kim, Yeji Lim, Taewon An, Hana Lee, Hae Mi Byun, Bojan Zaric
Journal: Journal of Clinical Oncology (2023)

Lazertinib is a potent, CNS-penetrant, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This global, phase III study (LASER301) compared lazertinib versus gefitinib in treatment-naïve patients with EGFR-mutated (exon 19 deletion [ex19del]/L858R) locally advanced or metastatic non-small-cell lung cancer (NSCLC).Patients were 18 years and older with no previous systemic anticancer therapy. Neurologically stable patients with CNS metastases were allowed. Patients were randomly assigned 1:1 to lazertinib 240 mg once daily orally or gefitinib 250 mg once daily orally, stratified by mutation status and race. The primary end point was investigator-assessed progression-free survival (PFS) by RECIST v1.1.Overall, 393 patients received double-blind study treatment across 96 sites in 13 countries. Median PFS was significantly longer with lazertinib than with gefitinib (20.6 v 9.7 months; hazard ratio [HR], 0.45; 95% CI, 0.34 to 0.58; P < .001). The PFS benefit of lazertinib over gefitinib was consistent across all predefined subgroups. The objective response rate was 76% in both groups (odds ratio, 0.99; 95% CI, 0.62 to 1.59). Median duration of response was 19.4 months (95% CI, 16.6 to 24.9) with lazertinib versus 8.3 months (95% CI, 6.9 to 10.9) with gefitinib. Overall survival data were immature at the interim analysis (29% maturity). The 18-month survival rate was 80% with lazertinib and 72% with gefitinib (HR, 0.74; 95% CI, 0.51 to 1.08; P = .116). Observed safety of both treatments was consistent with their previously reported safety profiles.Lazertinib demonstrated significant efficacy improvement compared with gefitinib in the first-line treatment of EGFR-mutated advanced NSCLC, with a manageable safety profile.
Menopausal hormone therapy and dementia: nationwide, nested case-control study
Authors: Nelsan Pourhadi, Lina S Mørch, Ellen A Holm, Christian Torp-Pedersen, Amani Meaidi
Journal: BMJ (2023)

Abstract Objectives To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage. Design Nationwide, nested case-control study. Setting Denmark through national registries. Participants 5589 incident cases of dementia and 55 890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy. Main outcome measures Adjusted hazard ratios with 95% confidence intervals for all cause dementia defined by a first time diagnosis or first time use of dementia specific medication. Results Compared with people who had never used treatment, people who had received oestrogen-progestin therapy had an increased rate of all cause dementia (hazard ratio 1.24 (95% confidence interval 1.17 to 1.33)). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for one year or less of use to 1.74 (1.45 to 2.10) for more than 12 years of use. Oestrogen-progestin therapy was positively associated with development of dementia for both continuous (1.31 (1.18 to 1.46)) and cyclic (1.24 (1.13 to 1.35)) regimens. Associations persisted in women who received treatment at the age 55 years or younger (1.24 (1.11 to 1.40)). Findings persisted when restricted to late onset dementia (1.21 (1.12 to 1.30)) and Alzheimer’s disease (1.22 (1.07 to 1.39)). Conclusions Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer’s disease, even in women who received treatment at the age of 55 years or younger. The increased rate of dementia was similar between continuous and cyclic treatment. Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.
A Critical Opportunity to Improve Public Health Data
Authors: David Blumenthal, Nicole Lurie
Journal: New England Journal of Medicine (2023)

Audio Interview Interview with David Blumenthal on opportunities to establish a national public health reporting system. 8m 46s Download AbstractDespite efforts to cobble together substitutes for a nationwide Covid data system, U.S. health authorities were flying blind for much of the pandemic. Pending legislation provides an opportunity to correct this shortcoming.
Perioperative Nivolumab and Chemotherapy in Stage III Non–Small-Cell Lung Cancer
Authors: Mariano Provencio, Ernest Nadal, José L González-Larriba, Alex Martínez-Martí, Reyes Bernabé, Joaquim Bosch-Barrera, Joaquín Casal-Rubio, Virginia Calvo, Amelia Insa, Santiago Ponce, Noemí Reguart, Javier de Castro, Joaquín Mosquera, Manuel Cobo, Andrés Aguilar, Guillermo López Vivanco, Carlos Camps, Rafael López-Castro, Teresa Morán, Isidoro Barneto, Delvys Rodríguez-Abreu, Roberto Serna-Blasco, Raquel Benítez, Carlos Aguado de la Rosa, Ramón Palmero, Florentino Hernando-Trancho, Javier Martín-López, Alberto Cruz-Bermúdez, Bartomeu Massuti, Atocha Romero
Journal: New England Journal of Medicine (2023)

Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients.In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety.A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%).In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).
Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort
Authors: Ehsan Irajizad, Johannes F. Fahrmann, Tracey Marsh, Jody Vykoukal, Jennifer B. Dennison, James P. Long, Kim-Anh Do, Ziding Feng, Samir Hanash, Edwin J. Ostrin
Journal: Journal of Clinical Oncology (2023)

To investigate the utility of integrating a panel of circulating protein biomarkers in combination with a risk model on the basis of subject characteristics to identify individuals at high risk of harboring a lethal lung cancer.
Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial
Authors: Bridie Thompson, Mary Waterhouse, Dallas R English, Donald S McLeod, Bruce K Armstrong, Catherine Baxter, Briony Duarte Romero, Peter R Ebeling, Gunter Hartel, Michael G Kimlin, Sabbir T Rahman, Jolieke C van der Pols, Alison J Venn, Penelope M Webb, David C Whiteman, Rachel E Neale
Journal: BMJ (2023)

Abstract Objective To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. Design Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. Setting Australia from 2014 to 2020. Participants 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking &gt;500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. Intervention 60 000 IU/month vitamin D 3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). Main outcome measures The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. Results 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (&lt;0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was −5.8 events per 1000 participants (95% confidence interval −12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). Conclusions Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. Trial registration ACTRN12613000743763
Mogamulizumab-induced bone granuloma: a multicentre nationwide case series
Authors: Florent Amatore, Delphine Darbord, Nathalie  Franck, Agnes Carlotti, Baptiste  Gillet, Aurelie Haffner, Stephanie Coze, Emmanuel  Delaporte, Ana  Carrasquilla-Capilla, Stephane Dalle, Olivier Dereure
Journal: British Journal of Dermatology (2023)

Our case series reports a new immune-related adverse event and highlights three important facts. Firstly, granulomatous reactions not only occur in the skin, but can also affect bones. Secondly, although possibly transient and spontaneously regressive, such lesions may result in protracted functional disabilities owing to their location and the interest of systemic steroids in this setting remains to be established. Finally, they should not be mistaken with an unfavourable evolution of the underlying disease and seem instead to be associated with protracted responses.